Cocaine abuse is one of the greatest concerns of the American public today, and has therefore become a focus of medical, social and political leaders. Cocaine is one of the most addictive substances known, and addicts may lose their ability to function at work or in interpersonal situations. Drug dependence and the great profits that are made throughout the distribution network of cocaine have fueled a rise in drug-associated crime in the United States and in Colombia. Although the incidence of casual cocaine use has decreased substantially in the last few years, the number of weekly users is rising. The rise has accompanied a change in the chemical form often used to free base, or xe2x80x9ccrack,xe2x80x9d and the route of administration used from nasal to inhalation by smoking or intravenous injection.
Psychological and behavioral approaches are important in a treatment program because peer pressure and environmental cues are closely associated with a relapse to addiction. However, behavioral observations have identified a window of about ten weeks after cessation of cocaine use where the susceptibility to relapse is greatest. Clearly, there is a need to increase the success rate of outpatient detoxification programs through the development of pharmacological agents that will assist during this critical period.
Currently a number of treatment strategies are being looked at using CNS agents developed for other indications. The agents being tried include, among others, the indirect dopamine agonist, amantadine, the direct agonist bromocriptine, the partial mu opiate receptor agonist, buprenorphine, and the tricyclic antidepressant, desipramine. While these agents appear to depress either self-administration or cocaine xe2x80x9ccravingxe2x80x9d under certain circumstances, these studies are still in their early stages and the efficacy of such treatments has not been established.
The behavioral properties of cocaine, including its abilities to act as a reinforcer, are thought to stem from its ability to inhibit the reuptake of dopamine (DA). While cocaine also has the ability to act as an inhibitor of serotonin and norepinephrine uptake as well as to bind to sigma opiate and muscarinic receptors, the potencies of cocaine and analogs in self-administration studies correlate best with their DA transporter inhibitor activities. Unfortunately, the precise mechanism by which cocaine inhibits dopamine uptake is still uncertain. Several laboratories have shown that cocaine inhibition of dopamine uptake into striatal synaptosomes is consistent with a classic, fully competitive mechanism. However these data are also consistent with more complex models, including allosteric or partially competitive, and several others involving steric hindrance, distinct but overlapping sites or multiple binding sites in which at least one is required for both cocaine and dopamine binding. In addition, a recent study using rotating disk electrode voltammetry, which is capable of monitoring uptake with a 50 msec resolution, suggests that cocaine inhibits dopamine uptake uncompetitively while competitively blocking Na+ and Clxe2x88x92 binding to the carrier. While these data have not been validated using other experimental approaches, they further support the idea that the cocaine and dopamine binding sites are unique.
N-Ethylmaleimide (NE) is capable of inhibiting about 95% of the specific binding of [3H]mazindol, and the effect of 10 mM N-ethylmaleimide is completely prevented by 10 xcexcM cocaine, while neither 300 xcexcM dopamine nor d-amphetamine afforded any significant protection. Furthermore, a recent study of the structure of the dopamine transporter revealed that aspartate and serine residues lying within the first and seventh hydrophobic putative membrane spanning regions were critical for dopamine uptake, but less so for [3H]CFT (WIN-35428) binding. For example, replacement of the serine residues at positions 356 and 359 in the seventh hydrophobic region by alanine or glycine reduced [3H]DA uptake, whereas [3H]CFT (WIN-35428) binding was less affected. More recent experiments with DA and NE transporter chimeras show that transmembrane domains 6-8 determine cocaine binding while domains 9-12 plus the carboxy tail are responsible for DA binding affinity. Thus, these data support the hypothesis that a significant portion of the cocaine binding domain on the dopamine transporter is distinct from that of either dopamine or amphetamine. This distinction may be sufficient to allow properly designed drugs to prevent cocaine binding without inhibiting dopamine uptake.
The most promising agents for treating cocaine abuse, may be agents which possess the ability to mimic partially the effects of cocaine, thereby helping to maintain individuals in treatment programs while they slowly withdraw from cocaine. Such an agent would function like methadone, a drug widely used in the treatment of opiate abuse. A compound with methadone-type activity against cocaine abuse is likely to be a partial agonist of cocaine; namely, a substance that elicits some of the same effects in the user as cocaine itself, but without causing the same degree of euphoria. Ideally, the compound should have little or no abuse liability.
Thus there is currently a need for safe and effective therapeutic agents for treating cocaine abuse.
The present invention provides a compound of formula (I):
Xxe2x80x94Lxe2x80x94X1xe2x80x83xe2x80x83(I)
wherein X and X1 are each independently a compound of formula II 
wherein:
Y is NR6, xe2x80x94C(R4)(R5)xe2x80x94, or xe2x80x94Oxe2x80x94;
R1 is xe2x80x94C(xe2x95x90O)ORa, cyano, (C1-C6)alkyl, (C1-C6)alkanoyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or 1, 2, 4-oxadiazol-5-yl optionally substituted at the 3-position by W, wherein any (C1-C6)alkyl, (C1-C6)alkanoyl, (C2-C6)alkenyl, or (C2-C6)alkynyl may optionally be substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, (C1-C6)alkoxy, (C2-C6)acyloxy, trifluoromethyl, C(xe2x95x90O)ORb, C(xe2x95x90O)NRcRd, NReRf, and S(xe2x95x90O)nRg; and R3 is (C6-C10)aryl, 5-10 membered heteroaryl, (C6-C10)aryl(C1-C6)alkyl, 5-10 membered heteroaryl(C1-C6)alkyl, (C6-C16)arylcarbonyl, biphenyl, or 5-10 membered heteroarylcarbonyl, wherein any aryl, biphenyl, or heteroaryl substituent may optionally be substituted on carbon with 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C2-C6)acyloxy, trifluoromethyl, C(xe2x95x90O)ORb, C(xe2x95x90O)NRcRd, NReRf, and S(xe2x95x90O)nRg; or
R1 is xe2x80x94CH2xe2x80x94, or xe2x80x94CH2CH2xe2x80x94, wherein R1 is attached to a carbon at the ortho position of R3; and R3 is (C6-C10)aryl, or 5-10 membered heteroaryl;
R2 is hydrogen or (C1-C6)alkyl;
R4 and R5 are independently hydrogen or (C1-C6)alkyl;
R6 is hydrogen, (C1-C6)alkyl, (C1-C6)alkanoyl, (C2-C6)alkenyl, (C2-C6)alkynyl, trifluoromethyl, aryl, heteroaryl, aryl(C1-C4)alkyl, heteroaryl(C1-C4)alkyl, aryl(C1-C4)alkanoyl, or heteroaryl(C1-C4)alkanoyl; wherein any (C2-C6)alkyl, (C2-C6)alkanoyl, (C2-C6)alkenyl, or (C2-C6)alkynyl may optionally be substituted on a carbon other than the carbon attached to the piperidine nitrogen with 1, 2 or 3 substituents independently selected from the group consisting of nitro, cyano, hydroxy, (C1-C6)alkoxy, (C2-C6)acyloxy, trifluoromethyl, C(xe2x95x90O)ORb, C(xe2x95x90O)NRcRd, and S(xe2x95x90O)nRg;
each n is independently 0, 1 or 2;
W is (C1-C6)alkyl, or aryl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, (C1-C6)alkoxy, (C2-C6)acyloxy, trifluoromethyl, C(xe2x95x90O)ORb, C(xe2x95x90O)NRcRd, NReRf, and S(xe2x95x90O)nRg;
Ra is hydrogen, (C1-C4)alkyl, aryl, heteroaryl, aryl(C1-C4)alkyl, or heteroaryl(C1-C4)alkyl;
each Rb is independently hydrogen, (C1-C4)alkyl, aryl, heteroaryl, aryl(C1-C4)alkyl, or heteroaryl(C1-C4)alkyl;
each Rc and Rd is independently hydrogen, (C1-C4)alkyl, aryl, heteroaryl, aryl(C1-C4)alkyl, or heteroaryl(C1-C4)alkyl; or, independently, each NRcRd together is piperidino, pyrrolidino, or morpholino;
each Re and Rf is independently hydrogen, (C1-C4)alkyl, (C1-C4)alkanoyl, (C1-C4)alkoxycarbonyl, aryl, heteroaryl, aryl(C1-C4)alkyl, heteroaryl(C1-C4)alkyl, aryl(C1-C4)alkanoyl, or heteroaryl(C1-C4)alkanoyl; or, independently, each NReRf together is piperidino, pyrrolidino, or morpholino;
each Rg is independently hydrogen, (C1-C4)alkyl, aryl, heteroaryl, aryl(C1-C4)alkyl, or heteroaryl(C1-C4)alkyl; and
L is an unbranched (C2-C12)alkylene chain, optionally substituted with one, two, or three substituents selected from the group consisting of (C1-C4)alkyl, (C1-C4)alkoxy, hydroxy, oxo, and halo; or L is an unbranched (C2-C10)alkylene chain comprising within the chain, at least, one divalent radical selected from the group consisting of non peroxide oxy (xe2x80x94Oxe2x80x94), thio (xe2x80x94Sxe2x80x94), sulfinyl, sulfonyl, xe2x80x94OC(xe2x95x90O)xe2x80x94, and xe2x80x94N(Rm)HC(xe2x95x90O)xe2x80x94; or L is Rixe2x80x94(C2-C10)xe2x80x94Rk wherein Ri and Rk are each independently xe2x80x94N(Rm)xe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94Sxe2x80x94; each Rm is hydrogen or (C1-C4)alkyl; and wherein L is attached to X and X1 at any chemically viable position;
or a pharmaceutically acceptable salt thereof.
In certain embodiments, the compounds of the present invention are represented by formulas I and II and the attendant definitions, wherein X is hydrogen; and L is absent.
Compounds of formula (I) and (II) bind to the cocaine recognition site with an affinity comparable to that of cocaine; additionally, the compounds act as potent inhibitors of dopamine uptake. In addition, certain compounds of formula (II) exhibit only weak cocaine- and amphetamine-like effects. Thus compounds of formula (I) and (II) partially mimic cocaine""s discriminative stimulus effects. There is evidence that the compounds are also non-addictive and have weak motor stimulant effects.
Based on the ability to bind cocaine recognition sites, the invention also provides a compound of formula I; or a pharmaceutically acceptable salt thereof, as an imaging agent. For example, the invention provides a radiolabeled compound comprising a radionuclide and a compound of formula I; or a pharmaceutically acceptable salt thereof, as well as methods for using such a radiolabeled compound as an imaging agent (e.g. to identify, or evaluate the function of, neurotransmitter binding sights in the brain of a mammal, such as a human).
The invention also provides a method comprising binding a compound of formula I to a mammalian tissue, which comprises dopamine receptors, in vivo or in vitro, by contacting said tissue with an amount of a compound of formula I effective to bind to said receptors. Tissue comprising dopamine receptors with compounds of formula I bound thereto can be used as a pharmacologic tool to identify potential therapeutic agents for the treatment of diseases or conditions associated with dopamine function, by contacting the agents with the tissue, and measuring the extent of displacement of the compound of formula I and/or binding of the agent. Tissue comprising dopamine receptors with compounds of formula I bound thereto can also be used generally to elucidate the physiological function of neurotransmitters.
The invention further features pharmaceutical compositions comprising an effective amount of a compound of formula I as described herein; or a pharmaceutically acceptable salt thereof; in combination with a pharmaceutically acceptable diluent or carrier.
Based on the ability of the compounds to bind to and prevent reuptake from both dopamine and serotonin receptors, the invention further features therapeutic methods, comprising administering a therapeutically effective amount of the claimed pharmaceutical compositions to a subject to treat or prevent a disease or condition that involves modulated or defective dopamine or serotonin transmission, including neurodegenerative diseases (including Parkinson""s disease and Alzheimer""s disease), depression, bipolar disorders, attention deficit disorder (ADD), and substance (e.g. cocaine) addiction.
Other features and advantages of the invention are set forth in the following detailed description and claims.